Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites. The consequence of this activity combines structural alteration of the extracellular matrix (ECM) underlying epithelial and endothelial cells, making it more susceptible to cellular invasion, and liberation of a multitude of biological mediators sequestered in the ECM or tethered to HS on the cell membrane.
Heparanase activity has long been associated with metastatic potential of tumor-derived cells (Vlodaysky, I., et al., 1983, Cancer Res 43, 2704-2711), a notion that has been established by employing specific anti-heparanase siRNA and ribozyme methodologies (Edovitsky, E., et al., 2004, J Natl Cancer Inst 96, 1219-1230).
Apart from the well studied enzymatic feature of the enzyme, heparanase was noted to exert biological functions apparently independent of its enzymatic activity. Inactive heparanase was noted to enhance adhesion and migration of normal and tumor-derived cells (Gingis-Velitski, S., et al., 2004, J. Biol. Chem. 279, 23536-23541; Goldshmidt, O., et al., 2003, FASEB J. 17, 1015-1025), and to promote the phosphorylation of signaling molecules such as Akt (Ben-Zaken, O., et al., 2007, Biochem Biophys Res Commun 361, 829-834; Doviner, V., et al., 2006, Mod Pathol 19, 878-888), likely supporting cell survival (Cohen, I., et al., 2006, Int J Cancer 118, 1609-1617). Similarly, enzymatically inactive heparanase was noted to enhance the phosphorylation of p38 and Src, associated with induced tissue factor (TF) and VEGF expression (Zetser, A., et al., 2006, Cancer Res 66, 1455-1463). More recently, heparanase was noted to augment the phosphorylation of EGFR in a Src-dependent manner. EGFR activation by heparanase was associated with enhanced cell proliferation and colony formation in soft agar. Furthermore, a correlation between heparanase and EGFR phosphorylation levels was found in head and neck carcinoma, positioning the heparanase-Src-EGFR axis as an important route in tumor progression.